KR20100015685A - Ranolazine for enhancing insulin secretion - Google Patents

Abstract

The invention is directed to methods for enhancing endogenous insulin levels in a patient in need thereof which method comprises administering to the patient an insulin secretion-enhancing amount of racemic ranolazine or the R-or S-enantiomer of ranolazine. It is also directed to methods of treatment comprising racemic ranolazine or the R-or S-enantiomer of ranolazine for enhancing endogenous insulin levels in a patient in need thereof. It is also directed to a composition comprising an insulin secretion-enhancing amount of racemic ranolazine or the R-or S-enantiomer of ranolazine and at least one anti-diabetic agent.

Description

Ranolazine for enhanced insulin secretion {RANOLAZINE FOR ENHANCING INSULIN SECRETION}

This application was filed on April 12, 2007. Provisional Patent Application Serial No. 60 / 911,457, filed U.S. Provisional Patent Application Serial No. 60 / 977,009, and U.S. Provisions are made to Provisional Patent Application Serial No. 61 / 026,223, which is incorporated herein by reference in its entirety.

The present invention requires endogenous insulin level enhancement, comprising administering to a patient an amount of ranolazine (racemate or (±)) or R- or S-enantiomer of ranolazine that enhances insulin secretion. A method of enhancing endogenous insulin levels in a patient. The present invention also relates to compositions and methods of treatment comprising ranolazine or R- or S-enantiomers of ranolazine for enhancing endogenous insulin levels in patients in need of endogenous insulin level enhancement.

Technology for the art

U.S. Patent 4,567,264, the entirety of which is incorporated herein by reference, includes ranolazine, (±) -N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2- Methoxyphenoxy) -propyl] -1-piperazineacetamide, and pharmaceutically acceptable salts thereof, and their in the treatment of cardiovascular diseases including arrhythmia, heteromorphic and motor-induced angina pectoris, and myocardial infarction Uses are disclosed. In the form of the dihydrochloride salt, ranolazine is represented by the formula:

The patent also discloses an intravenous (IV) formulation of dihydrochloride ranolazine further comprising propylene glycol, polyethylene glycol 400, Tween 80 and 0.9% saline.

U.S. Patent 5,506,229, the entirety of which is incorporated herein by reference, for the treatment of tissues suffering from physical or chemical damage, including hypoxia or reperfusion injury to heart failure, myocardial or skeletal muscle or brain tissue, and transplantation Use of ranolazine and its pharmaceutically acceptable salts and esters for use in water is disclosed. Oral and parenteral formulations are disclosed, including controlled release formulations. In particular, U.S. Example 7D of patent 5,506,229 describes a controlled release formulation in the form of a capsule comprising microspheres of ranolazine and microcrystalline cellulose, coated with a release controlling polymer. The patent also discloses an IV ranolazine formulation containing 5 mg ranolazine per milliliter of IV solution containing about 5% by weight dextrose at lower levels. Finally, at higher levels, an IV solution containing 200 mg ranolazine per milliliter of an IV solution containing about 4% by weight dextrose is disclosed.

The presently preferred route of administration of ranolazine and its pharmaceutically acceptable salts and esters is oral. Typical oral dosage forms are hard gelatin capsules filled with compressed tablets, powder mixes or granules, or soft gelatin capsules (softgel) filled with a solution or suspension. U.S. Patent 5,472,707, which is incorporated herein by reference in its entirety, discloses high dose oral formulations using supercooled liquid ranolazine as a fill solution for hard gelatin capsules or softgels.

U.S. Patent 6,503,911, the entirety of which is incorporated herein by reference, overcomes the problem of providing sufficient plasma levels of ranolazine while traveling through both the acidic environment in the stomach and the more basic environment through the intestine, Sustained release formulations have been disclosed that have proven to be very effective in providing plasma levels essential for the treatment of angina and other cardiovascular diseases.

U.S. Patent 6,852,724, which is incorporated herein by reference in its entirety, discloses methods for treating cardiovascular diseases including arrhythmia, dysplasia and motor-induced angina and myocardial infarction.

In US Patent Application Publication No. 2006/0177502, the entirety of which is incorporated herein by reference, an oral sustained release dosage form wherein 35% of ranolazine is present, preferably 40-45% of ranolazine. Is disclosed. In one embodiment the ranolazine sustained release formulation of the invention comprises a pH dependent binder; pH independent binders; And one or more pharmaceutically acceptable excipients. Suitable pH dependent binders include, but are not limited to, sufficient amounts of strong bases, such as sodium hydroxide, to neutralize the methacrylic acid copolymer by about 1-20%, for example about 3-6%, potassium hydroxide, or which partially neutralized with ammonium hydroxide methacrylic acid copolymer, for example the Eudragit ^® (Eudragit® L100-55, pseudo latex (pseudolatex) of Eudragit® L100-55, etc.). Suitable pH independent binders include, but are not limited to, hydroxypropylmethylcellulose (HPMC), for example Methocel® E10M Premium CR Grade HPMC or Methocel® E4M Premium HPMC. Suitable pharmaceutically acceptable excipients are magnesium stearate and microcrystalline cellulose (Avicel® pH101).

background

Insulin is secreted by the beta cells of the pancreas and is an essential hormone that lowers the concentration of glucose in the blood by stimulating glucose uptake and metabolism by muscle and adipose tissue. Insulin stimulates the storage of glucose as glycogen in the liver and triglycerides in adipose tissue. Insulin also promotes the use of glucose in the muscles as energy. Thus, insufficient blood insulin levels, or a decrease in sensitivity to insulin, can result in excessively high blood glucose levels.

Carbohydrates (or sugars) are absorbed by the intestine after meals and enter the bloodstream. The insulin is then secreted by the pancreas in response to this increase in blood sugar. Most cells in the body have insulin receptors that bind insulin in the circulation. When insulin attaches to receptors on the cell surface, glucose carriers designed to absorb glucose (sugar) from the bloodstream are activated. Since many of the somatic cells cannot use the calories contained in glucose without the action of insulin, without insulin, they can actually be starved, even if they consume a huge amount of food.

Diabetes is a metabolic disorder characterized by hyperglycemia (abnormally high blood glucose levels). There are two main types of diabetes: 1) type I, also known as insulin dependent diabetes, and 2) type II, also known as insulin independent diabetes. Generally, type II is referred to as “insulin independent diabetes”, but there are small groups of type II diabetic patients who can respond to enhanced insulin levels but do not produce enough insulin on their own.

Type I can be caused by genetic disorders. The source of type I is not fully understood and there are many theories. It is a chronic autoimmune disease characterized by extensive loss of beta cells on the island of Langerhans in the insulin producing pancreas. As these cells are progressively destroyed, insulin secretion decreases, and eventually insulin secretion falls below the level required for normal blood glucose (normal blood glucose levels), leading to hyperglycemia. Although the exact incentive for this immune response is unknown, all possible causes have the same end result: the pancreas produces little or no insulin.

In type II diabetes, the body does not produce enough insulin or the cells become resistant to insulin (response normally). In either case, glucose is absorbed by the cells and stays in the blood instead of undergoing metabolism. This failure to respond may be due to a decrease in the number of insulin receptors on the cell, or a dysfunction of the intracellular signaling pathways, or both. Beta cells in the pancreas initially compensate for this insulin resistance by increasing insulin production. Over time, these cells are unable to produce enough insulin to maintain normal glucose levels, resulting in type II diabetes.

When pancreatic beta cells fail to produce enough insulin, many problems arise. Increased blood glucose levels cause damage to nerves and blood vessels, mainly in the hands, feet, kidneys, eyes, and in other parts of the body. Other complications include heart disease, cardiovascular disease including coronary artery disease (CAD), and stroke.

High blood glucose levels cause thickening of the capillary basement membrane, which leads to gradual narrowing of the vessel lumina. Such vasculopathogy results in conditions such as diabetic retinopathy, coronary artery disease, capillary glomerulosclerosis, neuropathy, and ulcer formation and limb necrosis that can lead to blindness.

Toxic effects of excessive plasma glucose levels include glycosylation of cells and tissues. Glycosylated products accumulate in tissues, which can eventually form cross-linked proteins, which are referred to as advanced glycosylation end products. Nonenzymatic glycosylation is likely a direct cause for the expansion of the vascular matrix and vascular complications of diabetes. For example, glycosylation of collagen causes excessive crosslinking leading to atherosclerotic blood vessels. In addition, uptake of glycated proteins by macrophages stimulates the secretion of pro-inflammatory cytokines by these cells. The cytokines activate or induce degradation and proliferation cascades in mesenchymal and endothelial cells, respectively.

Thus, controlling blood glucose is a very desired therapeutic goal. One way of achieving this object is to provide a method of enhancing insulin secretion in a patient in need thereof.

U.S. Patent 4,567,264, the specification of which is incorporated herein by reference, includes (±) -N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2-methoxyphenoxy)- Propyl] -1-piperazineacetamide (known as ranolazine) compounds, and R- and S-enantiomers thereof, are disclosed. Ranolazine is approved for the treatment of chronic angina and has been shown to be an inhibitor of the late sodium channel. It has also been found to be useful in the treatment of congestive heart failure and arrhythmia. For example, U.S. Patents 6,528,511 and 6,677,342, and U.S. Pat. See Patent Publication No. 2003/0220344, the specification of which is incorporated herein by reference.

Although tolerability of ranolazine has been previously disclosed in diabetic patients (see US Patent Publication No. 2002/0052377), to date, the use of ranolazine in the treatment of diabetes has primarily led to HbA1c levels of ranolazine in patients receiving ranolazine. It was about the discovery that reduced it. For example, U.S. See Patent Publication No. 2004/0063717, the specification of which is incorporated herein by reference.

The present application discusses the treatment of all types of diabetes, including type I and type II, but ranolazine, particularly its R-enantiomer, enhances insulin secretion, leading to insulin-responsive and lack of insulin secretion. Unexpectedly found effective in treating diabetes in In addition, it was surprisingly found that the R-enantiomer of ranolazine also provided other pharmacokinetic benefits because of less inhibition on the CYP2D6 enzyme.

Accordingly, the present invention provides a method of enhancing endogenous insulin levels in a patient in need of enhancing endogenous insulin levels, comprising administering an amount of ranolazine or an R- or S-enantiomer of ranolazine that enhances insulin secretion. It is about. Additionally, the present invention also provides a method for treating patients suffering from one or more cardiovascular or heart disease symptoms comprising administering to the patients the S and / or R-enantiomers of ranolazine. It is directed to a method of reducing individual variation among patients while enhancing insulin levels and reducing all possible adverse events in patients with poor metabolism.

Summary of the Invention

In one aspect, the invention enhances endogenous insulin levels in patients in need of enhancing endogenous insulin levels, comprising administering an amount of ranolazine or an R- or S-enantiomer of ranolazine that enhances insulin secretion. Provide a method. Preferably, the patient is insulin-reactive and lacks insulin secretion.

In another aspect, the invention provides an amount and / or frequency of insulin administration to a patient comprising administering to the patient an amount of ranolazine or an R- or S-enantiomer of ranolazine that enhances insulin secretion. It provides a method of reducing.

In another aspect, the invention provides an amount of antidiabetic agent administration to a patient comprising administering to the patient an amount of ranolazine, or an R- or S-enantiomer of ranolazine, that enhances insulin secretion and Provide a method of reducing frequency.

In another aspect, the invention provides a method of preserving pancreatic beta cell function in a patient comprising administering to the patient an amount of ranolazine, or an R- or S-enantiomer of ranolazine, that enhances insulin secretion. To provide.

In another aspect, the present invention provides a method of treating a diabetic patient comprising administering to the patient an amount of ranolazine that enhances insulin secretion with at least one additional antidiabetic agent.

In another aspect, the present invention provides a composition comprising an amount of ranolazine that enhances insulin secretion and at least one additional antidiabetic agent.

In another aspect, the invention provides a method of enhancing endogenous insulin levels in a patient in need of enhancing endogenous insulin levels, comprising administering an R-enantiomer of ranolazine in an amount that enhances insulin secretion.

In another aspect, the present invention provides a method of enhancing endogenous insulin levels in a patient in need of enhancing endogenous insulin levels comprising administering an S-enantiomer of ranolazine in an amount that enhances insulin secretion.

In another aspect, the invention provides a method of reducing the amount and / or frequency of insulin administration to a patient, comprising administering to the patient an R-enantiomer of ranolazine in an amount that enhances insulin secretion. .

In another aspect, the invention relates to treating an insulin-resistant patient comprising administering to the patient an R-enantiomer of ranolazine in an amount that enhances insulin secretion with at least one additional antidiabetic agent. Provide a method.

In another aspect, the present invention provides a composition comprising an R-enantiomer of ranolazine in an amount that enhances insulin secretion and at least one additional antidiabetic agent.

The present invention is also, in part, a CYP2D6 inhibitor in which R-lanolazine is weaker than racemic ranolazine, and thus the possible use of the CYP2D6 enzyme when using R-lanolazine in the treatment of diabetes and / or one or more cardiovascular diseases. It relates to the discovery that it offers the possibility of reducing adverse events and / or drug-drug interactions caused by dysfunction and / or co-administration of CYP2D6 substrates.

In another aspect, the invention provides a method of treating a patient suffering from one or more cardiovascular diseases, comprising administering an R-enantiomer of ranolazine to these patients, wherein the adverse event and / or drug-drug interaction It relates to a method for reducing the.

In another aspect, the present invention provides a method of treating a patient suffering from one or more cardiovascular diseases comprising administering an R-enantiomer of ranolazine to these patients, the method of reducing adverse events in a patient. It is about.

In another aspect, the present invention provides a method of treating a patient suffering from one or more cardiovascular diseases comprising administering an R-enantiomer of ranolazine to these patients, the method comprising reducing drug-drug interactions in the patient. It is about how to let.

In another aspect, the invention relates to a method of treating a patient suffering from one or more cardiovascular diseases, wherein the patient is treated with the R-enantiomer of ranolazine without testing to determine if there is a malfunction of the CYP2D6 enzyme.

In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the R-enantiomer of ranolazine or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.

The present invention also relates, in part, to that S- ranolazine is a stronger inhibitor of beta adrenergic receptor receptors than racemic ranolazine, so that lower doses of S- ranolazine are therapeutically equivalent to racemic ranolazine. S- Ranolazine may be useful in reducing adverse events.

In another aspect, the present invention relates to a method for treating a patient suffering from one or more cardiovascular diseases, comprising administering an S-enantiomer of ranolazine to these patients, the method of reducing adverse events.

In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the S-enantiomer of ranolazine or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an R-enantiomer and an S-enantiomer of ranolazine or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof. It is about.

In another aspect, the invention also provides a method of treating a diabetic patient suffering from one or more cardiovascular diseases, reducing adverse events, wherein the therapeutically effective amount of R-ololazine R is different from that of the S-enantiomer. It relates to a method comprising administering an enantiomer.

Description of the Drawings

1 shows the effect of ranolazine on insulin secretion (GSIS) by glucose stimulation in pancreatic islets isolated from rats.

2 shows insulin levels during venous glucose tolerance test (IVGTT) performed in normal SD rats. In FIG. 2, □ is for ranolazine, and ○ is for vehicle.

FIG. 3 shows insulin for (±) ranolazine, R-enantiomer of ranolazine, and S-enantiomer of ranolazine (15 mg / kg) during intravenous glucose loading test (IVGTT) performed in normal SD rats. Shows the level. In Figure 3 ● is for the vehicle, 은 is for the R-enantiomer of ranolazine, and □ is for the S-enantiomer of ranolazine.

4 shows the R-enantiomer of ranolazine (denoted "R-"), the S-enantiomer of ranolazine (denoted "S-"), glucose (denoted "G"), and a positive control Shows the effect on GSIS in pancreatic islets isolated from humans (denoted "GLP1"). The number after the above description indicates the concentration of the compound (mM for “G” and μM for “R-” and “S-”).

5 shows the effect of (±) ranolazine on insulin secretion (GSIS) by glucose stimulation in pancreatic islets isolated from humans.

Detailed description of the invention

The present invention comprises administering an amount of ranolazine (racemate or (±)) or an R- or S-enantiomer of ranolazine to enhance insulin secretion, preferably to enhance endogenous insulin levels Provided are methods for enhancing endogenous insulin levels in patients in need thereof. The invention also provides compositions and methods of treatment comprising ranolazine or R- or S-enantiomers of ranolazine, which enhance insulin secretion in patients in need of enhanced insulin secretion.

Justice

In the present description and in the claims that follow, reference is made to a number of terms, which are defined to have the following meanings unless otherwise indicated.

When referred to as Ranexa®, "ranolazine" means (±) -N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2-methoxyphenoxy) propyl] -1 -Piperazine-acetamide compound. Ranolazine is also an enantiomer thereof (R)-(+)-N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2-methoxyphenoxy) -propyl]- 1-piperazinacetamide (also referred to as R-lanolazine), and (S)-(-)-N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- ( 2-methoxyphenoxy) -propyl] -1-piperazineacetamide (also referred to as S- ranolazine), and pharmaceutically acceptable salts thereof, and mixtures thereof. Unless otherwise stated, ranolazine plasma concentrations used in the present description and examples refer to ranolazine free base. At pH ˜4, in aqueous solution titrated with hydrogen chloride, ranolazine will most likely be present as its dihydrochloride salt.

N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2-methoxyphenoxy) propyl] -1-piperazinacetamide {also 1- [3- (2-methoxy Ranolazine, named phenoxy) -2-hydroxypropyl] -4-[(2,6-dimethylphenyl) -aminocarbonylmethyl] -piperazine} is a racemic mixture, or Enantiomers, or mixtures of enantiomers thereof, or pharmaceutically acceptable salts thereof. Ranolazine is U.S. It may be prepared as described in patent 4,567,264, the specification of which is incorporated herein by reference, and may also be purchased commercially. Enantiomers of ranolazine can be obtained using conventional methods such as chromatographic separation of racemic ranolazine or neosynthesis from chiral precursors.

"An effective amount to reduce bradycardia or bradyarrhythmia" is the amount of ranolazine that treats bradycardia or bradycardia.

"Physiologically acceptable pH" refers to the pH of an intravenous solution suitable for delivery into a human patient. Preferably, the physiologically acceptable pH range is about 4 to about 8.5, preferably about 4 to 7. Without wishing to be bound by any theory, it is considered physiologically acceptable to use an intravenous solution with a pH of about 4 to 6, where a large amount of blood in the body effectively buffers this intravenous solution.

"Cardiovascular disease" or "cardiovascular symptoms" includes, for example, heart failure, arrhythmia, exercise-induced angina, heterogeneous angina, including congestive heart failure, acute heart failure, ischemia, recurrent ischemia, myocardial infarction, STEMI and NSTEMI, etc. Refers to diseases or symptoms caused by angina, diabetes, and intermittent claudication, including stable angina, unstable angina, acute coronary syndrome, NSTEACS, and the like. Treatment for these disease states is described in U.S. Patents 6,503,911 and 6,528,511, U.S. Pat. Patent applications 2003/0220344 and 2004/0063717, the entire disclosures of which are incorporated herein by reference. Patents and patent applications are disclosed.

"Topical administration" will be defined as delivering a therapeutic agent to the wound and adjacent epithelial surfaces.

"Parenteral administration" is the systemic delivery of a therapeutic agent through injection to a patient.

"Substrate" refers to a compound that is metabolized by a given enzyme.

"Inhibitor" refers to a compound that "slows down" metabolism of a substrate. Inhibitors can be classified into strong, medium, and drug categories. Strong inhibitors include, for example, bupropion, fluoxetine, paroxetine, and quinidine, which are> 5 fold increase in plasma AUC levels or more than 80% decrease in clearance rate. May cause. Intermediate inhibitors include, for example, duloxetine and terbinafine, which can cause a> 2-fold increase in plasma AUC levels or a 50-80% decrease in clearance. Weak inhibitors include, for example, amiodarone and cimetidine, which can result in a> 1.25 fold but <2 fold increase in plasma AUC levels or a 20-50% decrease in clearance.

"Inducer" refers to a compound that "increases the rate" of metabolism of a substrate.

"Extensive metabolizer" or EM refers to a group of people who exhibit a normal response to a standard dose of a particular drug.

"Intermediate metabolizer" or IM may refer to a group of people who may have the problem of apoor metabolizer, but are usually not severe.

"Metabolizer" or PM refers to a group of people who are having problems handling standard doses of drugs because the gene fails to produce functional enzymes. Depending on the type of medicament, the drug may not be metabolized fast enough, resulting in side effects of standard dose overdose. Alternatively, the metabolic depressor may not be able to produce enough enzymes to convert the drug into its active form, and thus the standard dose may not have any therapeutic effect.

"Ultra metabolizer" or UM refers to a population of people who have one or more additional genes that produce the enzyme, producing more enzymes than normal. The extra enzymes that UM produces can be metabolized and removed from the body so quickly that standard doses may not have therapeutic benefit. Alternatively, the extra enzyme may convert the drug into its active form so quickly that the standard dose may be enhanced to toxic levels.

"Intermittent claudication" refers to pain associated with peripheral arterial disease. "Peripheral arterial disease" or PAD is a form of obstructive peripheral vascular disease (PVD). PAD affects the arteries outside the heart and brain. The most common symptom of PAD is painful cramps in the buttocks, thighs, or calves during walking, climbing, or exercising. The pain is called intermittent claudication. When listing intermittent claudication, we intended to include both PAD and PVD.

"Hazardous case (s)" refers to any unexpected or dangerous reaction to a drug.

“Arbitrarily” and “optionally” mean that an event or situation described subsequently may or may not occur, and the description includes cases where and when such an event or situation occurs. For example, "optional pharmaceutical excipients" may or may not include pharmaceutical excipients other than those stated to be expressly present in such formulations, and such formulations may include optional excipients. The presence and the absence of such excipients are included.

"Treating" and "treatment" refer to any treatment for a disease of a patient, including:

1. preventing the disease from occurring in a subject susceptible to the disease but not yet diagnosed;

2. inhibiting the disease, ie stopping further development thereof;

3. inhibit symptoms of the disease; Alleviate the disease, ie cause degeneration of the disease, or alleviate the symptoms of the disease.

"Patient" is a mammal, preferably a human.

The term “therapeutically effective amount” refers to an amount of a compound of formula I sufficient to effect a treatment, as defined below when administered to a mammal in need thereof. The therapeutically effective amount will vary depending on the specific activity of the therapeutic agent used and the age, physical condition, presence of other disease states, and nutritional status of the patient. In addition, other agents that may be on the patient will influence the determination of the therapeutically effective amount of the therapeutic agent to be administered.

As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

"Immediate release" ("IR") refers to a formulation or dosage unit that has been rapidly dissolved in vitro to allow complete dissolution and absorption in the stomach or upper gastrointestinal tract. Typically, such formulations release at least 90% of the active ingredient within 30 minutes after administration.

"Sustained release" ("SR") refers to a formulation or dosage unit as used herein which is slowly and continuously dissolved and absorbed in the stomach and gastrointestinal tract over a period of about 6 hours or more. Preferred sustained release formulations are those which exhibit a plasma concentration of ranolazine suitable for up to twice a day administration with up to 2 tablets per dose as described below.

"Isomers" are different compounds that have the same molecular formula.

"Stereoisomers" are isomers that differ only in the manner of atomic arrangement in space.

"Enantiomers" are stereoisomeric pairs that are mirror images that cannot overlap each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to indicate racemic mixtures where appropriate.

A "diastereomer" is a stereoisomer having at least two asymmetric atoms, but not mirror images of each other.

Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified as R or S. Separated compounds whose absolute configuration is not known are denoted as (+) or (-) depending on the direction (priority or leftness) of rotating the polarization plane at the wavelength of the sodium D line.

The term “lanolazine or R- or S-enantiomer of ranolazine” refers to the free base of any of these three compounds or the ester or salt of any of these three compounds. Esters or salts of any of these three compounds include, but are not limited to, U.S. It may be an ester or salt as named in patent 4,567,264, the specification of which is incorporated herein by reference.

The term “insulin” refers to any type of insulin, whether natural, synthetic, or recombinant, from any species and from any source, including cattle, sheep, pigs, horses, and preferably humans. The term "endogenous insulin" in a patient refers to insulin produced by islet cells in the pancreas of the patient.

The term “insulin-responsive” subject refers to:

a) a subject suffering from insufficient insulin levels, the subject being able to respond positively to insulin level enhancement, which is confirmed by a decrease in blood glucose levels in the subject after insulin level enhancement, or

b) Subjects suffering from failure to respond normally to insulin (insulin-resistance), subjects positively responding to insulin level enhancement, identified as a decrease in blood glucose levels in said subject after insulin level enhancement.

The term “lacking insulin secretion” refers to a subject capable of producing insulin in pancreatic islet cells but having impaired insulin release or production of the islet cells.

The term “maintaining effectiveness” of existing anti-diabetic treatment refers to reducing the need to increase or enhance the dose of existing antidiabetic agents. This also refers to reducing treatment failure with existing antidiabetic agents, thereby reducing the need to alter existing antidiabetic agents or add another antidiabetic agent.

The term “enhancing insulin secretion” refers to an amount sufficient to enhance the level of endogenous insulin secreted by pancreatic islet cells.

The term "anti-diabetic" agent refers to an agent that prevents or alleviates the symptoms of diabetes.

The term "anti-diabetic treatment" refers to a course of treatment with an anti-diabetic agent, wherein the anti-diabetic agent is as defined herein.

The term “pre-diabetic” patient refers to a patient with a glucose level higher than normal but not yet high enough to be diagnosed with diabetes or a patient with impaired glucose tolerance.

The term "prone to diabetes" refers to a person at high risk of developing diabetes. Many risk factors are known to those skilled in the art. Some of these factors include, but are not limited to, the following: genetic factors; Overweight (eg, body mass index (BMI) of at least 25 kg / m 2); Habitual physical inactivity; Race / ethnicity (eg, African American, Latin American, Native American, Asian American, Pacific Islander); Previously identified fasting glucose disorders or impaired glucose tolerance, hypertension (eg, 140/90 mm Hg or greater in adults); HDL cholesterol of at least 35 mg / dl; Triglyceride levels of at least 250 mg / dl; Gestational diabetes or a baby birth history of over 9 pounds; And / or polycystic ovary syndrome. See, eg, "Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus" and "Screening for Diabetes" Diabetes Care 2002, 25 (1), S5-S24.

Ranolazine may form acid and / or base salts in the presence of amino and / or carboxyl groups or groups similar thereto. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of ranolazine, which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases are, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary and tertiary amines such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di ( Substituted alkyl) amines, tri (substituted alkyl) amines, alkenyl amines, dialkyl amines, trialkenyl amines, substituted alkenyl amines, di (substituted alkenyl) amines, tri (substituted alkenyl) amines , Cycloalkyl amine, di (cycloalkyl) amine, tri (cycloalkyl) amine, substituted cycloalkyl amine, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amine, cycloalkenyl amine, di (cycloalkenyl) amine , Tri (cycloalkenyl) amine, substituted cycloalkenyl amine, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amine, aryl amine, diaryl amine, triaryl amine, heteroaryl amine, diheteroaryl amine , Triheteroaryl amine, hetero Click amines, diheterocyclic amines, triheterocyclic amines, at least two of the substituents for said amines are different and they are alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, Mixed di- and tri-amines selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines wherein the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.

Specific examples of suitable amines are, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri (iso-propyl) amine, tri (n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, Lysine, arginine, histidine, caffeine, procaine, hydramine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperi Dean et al.

Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p Toluene-sulfonic acid and salicylic acid.

As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

Method of the invention

The method of the present invention is based on the surprising finding that ranolazine and its enantiomers, in particular R-enantiomers, increase insulin secretion from pancreatic islets. Insulin secretion by the pancreas is controlled by a variety of factors, the most important of which is glucose.

Glucose metabolism produces various coupling factors that modulate the activity of the channels involved in the regulation of electrical activity and hence insulin secretion. Closure of K _ATP channels resulting from an increase in the ATP-ADP ratio results in membrane depolarization, and consequently activation of voltage dependent calcium channels, thereby creating a transmembrane action potential. Depolarization results in an increase in intracellular calcium, which plays a pivotal role in insulin secretion. Thus, changes in electrical activity are an essential intermediate step in GSIS (glucose stimulation of insulin secretion).

Without being bound by the theory of the present invention, any of the following five hypotheses may explain the effect of increasing GSIS of ranolazine or the R-enantiomer of ranolazine:

a) Ranolazine or R-enantiomer of _Ranolazine increases intracellular Ca ⁺⁺ by I _KATP inhibition and β-cell depolarization and thereby calcium channel activation, thereby increasing insulin release.

b) Granola photographic or granola spirit R- enantiomers, voltage switchgear St. K ⁺ channel one (K _VX (At this time, X represents a 2.1 or 2.2 or 3. The various subtypes of the K channel)), or any Inhibition of and by β-cell depolarization and thereby calcium channel activation increases intracellular calcium concentrations and then increases insulin release.

c) Ranolazine or the R-enantiomer of _ranolazine inhibits K _VX channels to prolong the action potential produced by β-cells due to glucose-induced inhibition of I _KATP , resulting in increased intracellular calcium and , Thus increasing insulin secretion.

d) Ranolazine or the R-enantiomer of _ranolazine increases the concentration of intracellular ATP by inhibiting I _Na and lowering ATP consumption, inhibiting I _KATP resulting in depolarization of β-cells, and then By activating calcium channels, intracellular calcium concentrations are increased, followed by increased insulin release.

e) Ranolazine or R-enantiomer of ranolazine can indirectly reduce Ca ⁺⁺ overload by inhibiting I _Na (peak or late) to reduce [Na ⁺ ] _I (intracellular sodium). .

f.) Ranolazine or R-enantiomers of ranolazine reduce long-term treatment by reducing pancreatic beta cell dysfunction, including Na ⁺ and Ca ²⁺ overload and induction of beta cell apoptosis and increased cell death. May increase insulin secretion.

g.) Ranolazine or the S- or R-enantiomer of ranolazine may contribute to increased insulin secretion by the alpha-adrenergic blocking effect.

In one embodiment, the invention comprises endogenous insulin in a patient in need of enhancing endogenous insulin levels, comprising administering to the patient an amount of ranolazine or an R- or S-enantiomer of ranolazine that enhances insulin secretion. Provides a way to enhance the level.

In another embodiment, the invention provides a method of enhancing endogenous insulin levels in a patient in need of enhancing endogenous insulin levels comprising administering to the patient an R-enantiomer of ranolazine in an amount that enhances insulin secretion. to provide.

In another embodiment, the present invention provides insulin administration to a patient that is insulin-responsive and lacking insulin secretion, comprising administering to the patient an amount of ranolazine or an R-enantiomer of ranolazine that enhances insulin secretion. A method of reducing the amount and / or frequency of an is provided.

In each of the above embodiments, the patient is preferably a patient that is insulin-responsive and lacks insulin secretion. The patient may be prediabetes or otherwise a patient prone to diabetes, or the patient may already be a patient with type II diabetes.

Special Characteristics of R-Enantiomers

As mentioned above, the process of the invention may be carried out using either ranolazine or one of the R- or S-enantiomers of ranolazine. However, the R-enantiomers are surprisingly and uniquely suited for use due to their unique properties. As discussed in Example 4 and as shown in FIG. 4, the R-enantiomers are significantly more effective in increasing insulin secretion in response to glucose. As a result, it is anticipated that the desired therapeutic effect may be achieved using a lower dose of R-enantiomer than is required for ranolazine or the S-enantiomer of ranolazine.

In addition, the R-enantiomers also exhibit pharmacokinetic advantages over ranolazine or the S-enantiomer of ranolazine. The inhibitory effect of ranolazine on CYP2D6 was evaluated in a wide range of metabolites for dextromethorphan. The study showed that ranolazine and / or metabolites partially inhibited CYP2D6. The use of ranolazine in combination with other drugs metabolized by CYP2D6, such as tricyclic antidepressants and antipsychotics, has not been officially studied, but in the presence of ranolazine there are fewer doses of these drugs than those normally prescribed. It may be necessary. Ranolazine can inhibit the activity of CYP2D6, and thus increases the exposure to these drugs, primarily due to impaired metabolism of drugs that are metabolized by the enzymes, such as tricyclic antidepressants and some antipsychotics. Can be. When co-administering ranolazine, it may be necessary to reduce the dose of these drugs.

Cytochrome P450 (CYP) generally contains major enzymes that cause oxidative metabolism of drugs. CYP isoenzyme, CYP2D6, specifically has a wide range of activity in the human population, with metabolic rates of more than 10,000 times between individuals. Most people are broad metabolizers (EMs) capable of extensive metabolism of CYP2D6 substrates, while 7-10% of whites are metabolic depressors (PM) that do not produce functional CYP2D6 enzymes. Metabolic depressors account for 2-10% across all groups, including Asians and African-Americans.

DNA polymorphisms have been identified in genes encoding a number of CYP isozymes, which lead to wide interpersonal variations in drug clearance. CYP2D6 metabolizes a significant number of clinically used drugs, and genetic variants of CYP2D6 isozymes that cause diversification of metabolic activity levels are clinically important in some circumstances. Since different variants produce different phenotypes with a range of enzyme activity levels, the exact nature of the clinical effect caused by the polymorphism of the gene depends on the drug and the particular variant allele expressed.

Interpersonal variation in drug metabolism presents challenges in predicting drug dose, safety and efficacy. For example, pharmacokinetic factors, and significant pharmacokinetic variations between subjects, have been suggested as one factor in the case of treatment failure of methylphenidate. DeVane, et al., Journal of Clinical Psychopharmacology, 20 (3), 347 (2000)]

A person who lacks the expression of a polymorphic drug-metabolizing enzyme (usually referred to as "metabolizer" or PM) will have higher drug exposure in the body if the drug is metabolized by these polymorphic enzymes, which is a medium given the same dose. Metabolic and widespread metabolic (EM) subjects can result in excessive pharmacological or side effect enhancement. Alternatively, when the polymorphic enzymes form certain metabolites that contribute to the activity of the drug, different efficacy profiles can be observed in EM and PM patients. Gibbs, et al., Drug Metabolism and Disposition 34 (9), 1516-1522 (2006)]

Of the polymorphic enzymes found to be involved in drug metabolism, CYP2D6 with formal substrate specificity for many new chemicals is considered one of the most important. It is estimated that 20-25% of all drugs for clinical use are at least partially metabolized by CYP2D6. The frequency of CYP2D6 PM in the population is race-dependent and is reported to be approximately 1% in Asians and 5-10% in Caucasians [Gibbs, et al., Drug Metabolism and Disposition 34 (9), 1516-1522 (2006)]. . The primary liver expression of these enzymes dominates first pass metabolism after oral drug administration, and low levels of intestinal expression do not seem important. A number of studies have characterized the effect of CYP2D6 polymorphism on substrate area (AUC) under the concentration curve in EM and PM subjects.

Known cardiovascular drug substrates for CYP2D6 include, but are not limited to:

Antiarrhythmic agents: amiodarone, encainide, flecainide, lidocaine, and mexiletine;

Antihypertensives: captopril, clonidine, debrisoquine, gaunoxan, indapamide, N-propylajmaline, procaineamide ), Propafenone, and spartein;

Beta blockers: alprenolol, bisoprolol, bufuralol, bufurolol, bupranolol, carvedilol, labetalol, metoprolol, pindolol pindolol, propanolol, and timolol;

Calcium channel blockers: cinnarizine, flunarizine, nimodipine, nitrendipine, and perhexiline; And

Antidiabetic drugs: phenformin.

Although it is known that the metabolic lowering phenotype is caused by two null alleles resulting in the absence of functional CYP2D6 protein, many variability among people with functional alleles remains largely unexplained.

Many drug interactions result from inhibition (eg, by competing for the same enzyme binding site) or induction (increase in enzyme protein synthesis) for CYP enzymes. Unlike other CYP isoenzymes, CYP2D6 is not considered to be inducible (eg, by drugs such as riampicin). However, it is vulnerable to inhibition. Some drugs, such as paroxetine, inhibit CYP2D6 strongly enough to convert up to 80% of EM into PM, ie, significantly reduce the ability of CYP2D6 substrate metabolism. Other strong CYP2D6 inhibitors include fluoxetine, terbinafine and thiolidazine. Weaker inhibitors include tricyclic antidepressants and citalopram.

In general, PMs have higher parent drug concentrations, which can result in toxic concentrations by standard doses. In some cases, if the CYP2D6 metabolite is more active than the parent compound, reduced drug effect may occur due to reduced production of the active metabolite. Ultra-rapid metabolites remove CYP2D6 substrates very quickly and may not be able to achieve therapeutic concentrations at standard doses.

Thus, there is a strong advantage in using drugs that exhibit reduced inhibition on CYP2D6. When administered to a patient suffering from one or more cardiovascular or cardiac disease symptoms, the use of such agents reduces inter-individual variation among patients and reduces possible adverse events in patients with metabolic lowering. Reduced inhibition of CYP2D6 may also reduce the interpersonal variation seen between patients and metabolism, if a combination of drugs for cardiovascular symptoms is prescribed for the patient, especially if the combination of drugs is metabolized via CYP2D6 It is possible to reduce possible adverse events in low-grade patients.

As discussed in Examples 6 and 7, the R-enantiomer of ranolazine was shown to inhibit CYP2D6 to a much lesser extent than either ranolazine or the S-enantiomer of ranolazine.

Taking into account the surprising advantages presented by the R-enantiomer, both in terms of its ability to increase glucose-induced insulin excretion, which is increased in the R-enantiomer, and in its ability to inhibit CYP2D6, which is reduced therein, In a aspect, the present invention provides a method of treating a patient suffering from one or more cardiovascular disease or cardiovascular disease symptoms comprising administering an R-enantiomer of ranolazine to these patients, wherein the possible dysfunction of the CYP2D6 enzyme Methods of reducing the adverse events and / or drug-drug interactions that are caused are provided.

Patients exhibiting one or more cardiovascular disease cases or symptoms include, but are not limited to, patients being treated for one or more of the following: stable angina, unstable angina (UA), exercise-induced angina, heterotypic angina Angina, arrhythmia, intermittent claudication, myocardial infarction, including STEMI and non-STE myocardial infarction (NSTEMI), congestive (or chronic) heart failure, heart failure, including acute heart failure, or recurrent ischemia.

Other conditions treatable using the methods of the invention include, but are not limited to: heart failure, including congestive heart failure, acute heart failure, myocardial infarction, and ventricular tachycardia such as atrial fibrillation, atrial fibrillation , Treatment of ventricular tachycardia (VT), including AV nodular regressive tachycardia, atrial tachycardia, and idiopathic ventricular tachycardia, ventricular fibrillation, early-excited syndrome, and Torsade de Pointes (TdP) Peripheral artery disease including arrhythmia, exercise-induced angina, heterogeneous angina, stable angina, unstable angina, acute coronary syndrome, and the like, and intermittent claudication.

Special Characteristics of S-Enantiomers

While R-enantiomers are well suited for use in the methods of the present invention, it should be noted that S-enantiomers also have unique properties that make them ideal for use as anti-ischemic and antiarrhythmic agents. As discussed in Examples 8, 9, and 10, the S-enantiomer of ranolazine has a later sodium channel, I _Kr , β ₁ -AR, and β ₂ than either the R-enantiomer or racemic ranolazine. It is a more potent inhibitor of -AR. As a result, the S-enantiomer is a potentially stronger and better antianginal and antiarrhythmic drug than either the R-enantiomer or racemic ranolazine.

In view of the different properties of the two enantiomers, it is another aspect of the present invention to provide a dosage form comprising both R- and S-enantiomers of ranolazine in unequal amounts. The advantage of such non-racemic combinations is that the skilled artisan can treat patients suffering from insulin deficiency, patients suffering from cardiovascular disease, or both by varying the amount of either the S- or R-enantiomer. It is possible to prepare formulations that provide better efficacy.

Based on the surprising advantages presented by the S-enantiomers with respect to increased efficacy on cardiovascular manifestations, in another aspect, the present invention provides a therapeutically effective minimum dose of the S-enantiomer of ranolazine to a patient. A method of treating a patient suffering from one or more cardiovascular disease or cardiovascular disease symptoms comprising administering, the method of reducing adverse events is provided.

Co-administration

According to the present invention, ranolazine or the R- or S-enantiomer of ranolazine in combination with another antidiabetic agent, or more than one, for treating diabetes and / or improving glycemic control in a patient in need thereof. Can be used in combination with antidiabetic agents. The compounds may be administered separately, or may be combined in a single formulation such as tablets, capsules, syrups, solutions, and formulations as controlled release formulations. The dosage of each agent will vary depending on the severity of the disease, the frequency of administration, the specific agent and combination used, and other factors routinely considered by the attending physician.

Thus, in another embodiment, the present invention provides a method for treating a patient that is insulin-responsive and lacks insulin secretion, in which the amount of ranolazine or the R-enantiomer of ranolazine for enhancing insulin secretion is at least one antidiabetic. Provided is a method comprising administering to a patient in combination with an agent.

In another embodiment, the present invention provides a method for maintaining the effectiveness of anti-diabetic treatment in a patient, comprising combining ranolazine or an R-enantiomer of ranolazine with an amount that enhances insulin secretion in combination with the antidiabetic agent. Provided is a method comprising administering to a patient.

In another embodiment, the present invention provides a composition comprising ranolazine or an R-enantiomer of ranolazine and at least one antidiabetic agent in an amount that enhances insulin secretion.

In another embodiment, the invention also provides a method comprising co-administering ranolazine or an R-enantiomer of ranolazine and at least one antidiabetic agent in an amount that enhances insulin secretion. Co-administration is the combination of a single formulation (eg, ranolazine or R-enantiomer of ranolazine and another antidiabetic agent with a pharmaceutically acceptable excipient, optionally combining the two active ingredients These respective release rates and durations can be separated into different excipient mixtures designed to be controlled independently) or by independently administering separate formulations containing the active agents.

"Co-administration" also includes co-administration (R-enantiomer of ranolazine or ranolazine and other anti-diabetic agents simultaneously) and time-differentiated administration (R-enantiomer of ranolazine or ranolazine). Administration at a different time than the diabetic agent) provided that the ranolazine or R-enantiomer of ranolazine and other antidiabetic agents are all present at therapeutically effective concentrations in the serum for at least partially overlapping. .

Thus, in some aspects, ranolazine or the R-enantiomer of ranolazine and the antidiabetic agent (s) may be administered in a single formulation. In some other aspects, the ranolazine or R-enantiomer of ranolazine and the antidiabetic agent (s) are administered separately but simultaneously. In some other aspects, the ranolazine or R-enantiomer of ranolazine and the antidiabetic agent (s) are individually but sequentially administrable.

In some aspects, the antidiabetic agent is sulfonylurea, DPP-IV inhibitor, biguanide, thiazolidinedione, alpha-glucosidase inhibitor, incretin mimetic, PPAR gamma modulator, dual PPAR alpha / gamma agonist, RXR modulator, SGLT2 inhibitor, aP2 inhibitor, insulin sensitizer, PTP-IB inhibitor, GSK-3 inhibitor, DP4 inhibitor, insulin sensitizer, insulin, meglitinide, PTP1B inhibitor, glycogen phosphorylase inhibitor, glucose -6-phosphatase inhibitors, and amylin analogues.

Examples of sulfonylureas include, but are not limited to, tolbutamide, tolazamide, acetohexamide, chlorpropamide, glyburide, glyph Glipizide, glimepiride, gliclazide, gliquidone, and the like. Examples of biguanides include, but are not limited to, metformin, phenformin, and the like. Examples of meglitinides include, but are not limited to, repaglinide, nateglinide, and the like. Examples of PPAR gamma modulators include, but are not limited to, thiazolidinediones such as rosiglitazone, pioglitazone, troglitazone and the like. Examples of alpha-glucosidase inhibitors include, but are not limited to, miglitol, acarbose, and the like. Examples of incretin mimetics include, but are not limited to, exenatides. Examples of DPP-IV inhibitors include, but are not limited to, bildagliptin, sitagliptin, and the like. Examples of amylin analogs include, but are not limited to, pramlintide.

In some preferred aspects, the invention comprises ranolazine or an R-enantiomer of ranolazine and at least one antidiabetic agent in an amount that enhances insulin secretion, wherein the antidiabetic agent is metformin, phenformin , Buformin, chlorpropamide, glisoxepid, glyburide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, article Lipidide, Glymepiride, Glyclazide, Glyquidone, Glyhexamide, Phenbentamide, Tolcylamide, Troglitazone, Pioglitazone, Rosiglitazone, Migitol, Acarbose, Exenatide, Provided is a composition selected from the group consisting of bilagliptin, cytagliptin, repaglinide, pramlinide, and nateglinide.

Usability Testing and Administration

General usability

The method of the invention is useful for increasing insulin secretion by glucose stimulation in patients who are insulin-reactive and lacking insulin secretion. The method is also useful in connection with the R-enantiomer of ranolazine, including, for example, heart failure, arrhythmia, exercise, including congestive heart failure, acute heart failure, ischemia, recurrent ischemia, myocardial infarction, STEMI and NSTEMI, and the like. It is effective for treating mammals for various disease states such as angina pectoris, diabetes, and intermittent claudication, including induced angina, heterogeneous angina, stable angina, unstable angina, acute coronary syndrome, NSTEACS and the like.

Pharmaceutical Compositions and Administration

Ranolazine or the R- or S-enantiomer of ranolazine is usually administered in the form of a pharmaceutical composition. The present invention therefore provides carriers, sterile aqueous solutions and various organic solvents comprising, as active ingredients, ranolazine, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, inert solid diluents and fillers. It provides a pharmaceutical composition containing a diluent, a solubilizer and an adjuvant. Ranolazine may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, eg, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3rd Ed) (GS Banker & CT.Rhodes, Eds.).

Ranolazine or the R- or S-enantiomer of ranolazine is incorporated into any acceptable dosage form of a formulation with similar uses, including, for example, rectal, buccal, intranasal and transdermal routes, for example incorporated by reference. As described in patents and patent applications, intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, by inhaler, or, for example, such as a stent It can be administered in single or multiple doses, via injection or coating equipment or cylindrical polymers inserted into arteries.

Suppositories, Suspensions, Sub-Q, and Topical Formulations

Representative examples of suppositories, suspensions, subcutaneous formulations, and topical formulations are as follows.

Suppositories containing 25 mg of each active ingredient can be prepared as follows:

ingredient amount Active ingredient 25 mg Saturated Fatty Acid Glyceride Amount to be 2,000 mg

The active ingredient is No. 60 mesh U.S. Pass through a sieve and suspend in pre-melted saturated fatty acid glycerides using the minimum heat required. The mixture is then poured into a suppository frame of nominal 2.0 g capacity and cooled.

Suspensions containing 50 mg of active ingredient per 5.0 mL dose each can be prepared as follows:

ingredient amount Active Ingredient Xanthan Gum Sodium Carboxymethyl Cellulose Microcrystalline Cellulose Sucrose Sodium Benzoate Flavoring Agent and Colorant Purified Water 50 mg 4.0 mg 11% 50 mg 1.75 g 10.0 mg Random amount 5.O mL

Blending the active ingredient, sucrose and xanthan gum, 10 mesh U.S. After passing through a sieve, it is mixed with a solution of microcrystalline cellulose and sodium carboxymethyl cellulose previously prepared in water. Sodium benzoate, flavors, and colorants are diluted with some water and added with stirring. Then sufficient water is added to make the required volume.

Subcutaneous formulations can be prepared as follows:

ingredient amount Active ingredient 5.0 mg Corn oil 1.0 mL

Topical formulations of the following compositions can be prepared:

ingredient Volume (grams) Active Ingredient Span 60 Tween 60 Mineral Oil Petrolatum Methyl Paraben Propyl Paraben BHA (Butylated Hydroxy Anisole) Water Enough to be 0.2-10 2.0 2.0 5.0 0.10 0.15 0.05 0.01 100

All the above ingredients except water are combined and heated to 60 ° C. with stirring. Thereafter, a sufficient amount of water at 60 ° C. is added with vigorous stirring to emulsify the components, and then in a sufficient amount to bring 100 g of water.

Oral Formulations

Oral administration is the preferred route of ranolazine and R- or S-enantiomers of ranolazine. Administration can be through capsules or enteric coated tablets or the like. In the preparation of a pharmaceutical composition comprising ranolazine, or the R- or S-enantiomer of ranolazine, the active ingredient is usually diluted with excipients and / or may be in the form of capsules, sachets, paper or other containers. Contained in a carrier. If the excipient functions as a diluent, it may be a solid, semisolid or liquid substance (as described above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be used in tablets, pills, powders, lozenges, cachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, (as a solid or in a liquid medium). Aerosols, ointments containing up to 50% by weight of active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

Representative examples of capsules and tablets are as follows.

Hard gelatin capsules may be prepared containing the following ingredients:

ingredient Volume (mg / capsule) Active Ingredient Starch Magnesium Stearate 30.0 305.0 5.0

The ingredients are mixed and filled into hard gelatin capsules.

Tablet formulations may be prepared using the following ingredients:

ingredient Volume (mg / tablet) Active ingredient Cellulose, microcrystalline colloidal silicon dioxide stearic acid 30.0 305.0 5.0 5.0

The components are blended and compressed to form tablets.

Tablets containing 30 mg of each active ingredient can be prepared as follows:

ingredient Volume (mg / tablet) Active Ingredient Starch Microcrystalline Cellulose Polyvinylpyrrolidone (as a 10% solution in sterile water) Sodium Carboxymethyl Starch Magnesium Stearate Talc Gun 30.0 mg 45.0 mg 35.0 mg 4.0 mg 4.5 mg 0.5 mg 1.0 mg 120 mg

The active ingredient, starch and cellulose were No. 20 mesh U.S. Pass through a sieve and mix thoroughly. The resulting powder was mixed with a solution of polyvinylpyrrolidone, which was then 16 mesh U.S. Pass it through a sieve. The granules so prepared are dried at 50 ° C. to 60 ° C. and 16 mesh U.S. Pass the sieve. After that, No. 30 mesh U.S. Sodium carboxymethyl starch, magnesium stearate, and talc pre-passed through a sieve are added to the granules, mixed and compressed on a tableting machine to produce tablets each weighing 120 mg.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose , Sterile water, syrup, and methyl cellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate, and mineral oil; Wetting agents; Emulsifying and suspending agents; Preservatives such as methyl- and propylhydroxy-benzoate; Sweeteners; And flavoring agents.

To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the invention. When referring to these preformulation compositions as homogeneous, it is intended that the active ingredients are evenly distributed throughout the composition so that the composition can be easily divided into uniformly effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwise formulated for the purpose of providing a dosage form with the advantage of prolonging action or for protection against acidic conditions above. For example, the tablet or pill may comprise internal and external administration components, with the latter enclosing the former. The two components can be separated by an enteric layer that functions to prevent disintegration in the stomach and to enter the duodenum without delaying the internal components or to delay release. A variety of materials can be used as such enteric layers or coatings, including a mixture of a number of polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

Formulations for Inhalation or Insufflation

Compositions for inhalation or aeration include solutions and suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described above. Preferably the composition is administered by oral or nasal respiratory route for local or systemic effects. Preferably the composition in a pharmaceutically acceptable solvent can also be nebulized with an inert gas. The spray solution may be inhaled directly from the spray apparatus or the spray apparatus may be attached to a face mask tent, or an intermittent positive pressure respirator. Solutions, suspensions, or powder compositions may also be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasal.

Representative examples of dry powder inhaler formulations may be prepared containing the following components:

ingredient weight% Active ingredient lactose 5 95

The active ingredient is mixed with lactose and the mixture is added to a dry powder inhalation device.

Parenteral administration

One dosage form is parenteral, in particular by injection. Forms which may incorporate the novel compositions of the present invention for administration by injection include sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceuticals. Emulsions containing vehicles or aqueous or oil suspensions are included. Aqueous solutions in saline are also commonly used for injection, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils are also available. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.

Sterile injectable solutions are prepared by incorporating the compound of the invention in the required amount in the appropriate solvent with the various other ingredients enumerated above, as required, followed by filtration and sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is a vacuum-drying and freeze-drying technique, which produces a powder of the active ingredient plus any additional ingredients desired from the immediately preceding sterile-filtration solution.

Representative examples of injectable preparations may be prepared having the following compositions:

ingredient amount Active Ingredient Mannitol, USP Gluconic Acid, USP Water (Distilled, Sterile) Nitrogen Gas, NF 2.0 mg / mL 50 mg / mL Sufficient (pH 5-6) Sufficient to be 1.0 mL Sufficient

IV administration and stents

Intravenous formulations of ranolazine or R- or S-enantiomers of ranolazine are prepared via a sterile filling process as follows. In a suitable container, the required amount of dextrose monohydrate is dissolved in approximately 78% of the water for injection (WFI) of the final batch weight. With continued stirring, the required amount of ranolazine free base is added to the dextrose solution. To facilitate dissolution of ranolazine, the solution pH is adjusted to 3.88-3.92 with 0.1N or 1N hydrochloric acid solution. Additionally, the solution may be final adjusted to a target pH of 3.88-3.92 with 0.1 N HCl or 1.0 N NaOH. After dissolving ranolazine, the batch is adjusted to final weight using WFI. Once the in-process specification has been met, the ranolazine or R- or S-enantiomer bulk solution of ranolazine is sterilized by sterile filtration through two 0.2 μm sterile filters. The sterile ranolazine or R- or S-enantiomer bulk solution of ranolazine is then aseptically filled into sterile glass vials and closed aseptically with sterile stoppers. The stoppered vial is then sealed with a clean flip-top aluminum seal.

Ranolazine or the R- or S-enantiomer of ranolazine is injected into the stent using procedures known to those skilled in the art in view of the present disclosure, eg, using diffusion, or, eg, a gel It may be coated on the stent in the form or the like.

Unit dosage form

It is preferred to formulate the composition in unit dosage form. The term "unit dosage form" means suitable in single dosages for human patients and other mammals, each containing a predetermined amount of active substance calculated with the desired therapeutic effect, together with suitable pharmaceutical excipients, Refers to physically discrete units (eg, tablets, capsules, ampoules).

Ranolazine or R- or S-enantiomers of ranolazine are effective over a wide range of administration and are generally administered in pharmaceutically effective amounts. Preferably, for oral administration, each dosage unit comprises from 10 mg to 3 g of ranolazine or ranolazine of R- or S-enantiomer, more preferably R- or S- of ranolazine or ranolazine. 10 mg to 2 g, more preferably 10 mg to 1500 mg, more preferably 10 mg to 1000 mg, more preferably 10 mg to 700 mg, and for parenteral administration, the enantiomer is preferably 10 mg to 700 mg, more preferably about 50 mg to 200 mg.

However, the actual dosage of ranolazine or the R- or S-enantiomer of ranolazine depends on the condition being treated, the route of administration chosen, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the symptoms of the patient. It will be appreciated that the decision will be made by the physician in light of the severity and the related circumstances. Unit dosage forms will typically be administered once, twice, three or four times daily. The unit dosage form may be taken before, with or after a meal.

Immediate and sustained release

In one embodiment, using the procedures known in the art, particularly sustained release of the ranolazine or R- or S-enantiomer of ranolazine, such that the active ingredient is released rapidly, continuously or delayed after administration to the patient. Formulations are provided to provide a formulation. Unless otherwise stated, the ranolazine concentration in plasma used in the present description and examples refers to ranolazine or the R- or S-enantiomer free base of ranolazine. Controlled release drug delivery systems for oral administration include dissolution systems and osmotic pump systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Patent number 3,845,770; 4,326,525; 4,902,514; And 5,616,345.

It is contemplated to formulate ranolazine or the R- or S-enantiomer of ranolazine to produce a combination of immediate release and sustained release or delayed release form. In such embodiments, the sustained release or controlled release core may be covered with an immediate release layer. Formulations of this type would be advantageous if taken before a large amount of meal, since they could then be sustained release and increase insulin secretion in response to the meal immediately after administration. Coatings and core formulations of this type may also be used to prepare formulations comprising one or more antidiabetic agents as discussed above.

Another formulation used in the method of the invention utilizes a transdermal delivery device (“patch”). Such transdermal patches can be used to continuously or discontinuously inject the compounds of the invention in controlled amounts. The construction and use of transdermal patches for delivery of pharmaceutical agents are well known in the art. For example, U.S. See patents 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructed to deliver pharmaceuticals continuously, pulsating or on demand.

Preferred sustained release formulations of the invention preferably have a partially neutralized pH that controls the dissolution rate in an aqueous medium over the pH range in the stomach (typically about 2) and in the intestine pH range (typically about 5.5). It is a form of compressed tablet containing an intimate mixture of dependent binders and compounds. Examples of sustained release formulations are described in U.S. Pat. Patent 6,303,607; 6,479,496; 6,369,062; And 6,525,057, the entirety of which is incorporated herein by reference.

To provide a sustained release formulation of ranolazine or an R- or S-enantiomer of ranolazine, one or more pH-dependent binders may be used to slow down the drug as the formulation passes through the stomach and gastrointestinal tract. It is chosen to adjust the dissolution profile of the compound to sustained release. The ability to control the dissolution of the pH-dependent binder (s) is particularly important in sustained release formulations, because sustained release formulations containing enough compounds for two daily administrations are released when the compound is released too quickly (“dose” "Dose-dumping") can cause bad side effects.

Thus, pH-dependent binders suitable for use in the present invention inhibit rapid release of the drug from the tablet during residence in the stomach (pH is less than about 4.5) and lower gastrointestinal tract (pH is generally greater than about 4.5). ) Promote the release of a therapeutic amount of a compound from the dosage form. Many of the materials known in the pharmaceutical art as "entertaining" binders and coatings have the above preferred pH eluting properties. These include phthalic acid derivatives such as phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkyl celluloses, alkyl celluloses, cellulose acetates, hydroxyalkyl cellulose acetates, cellulose ethers, alkyl cellulose acetates, and partial esters thereof, and lower alkyl acrylic acids. And polymers and copolymers of lower alkyl acrylates, and partial esters thereof.

A preferred pH-dependent binder material that can be used with the compound for the production of sustained release formulations is methacrylic acid copolymer. Methacrylic acid copolymers are copolymers of methacrylic acid with neutral acrylate or methacrylate esters such as ethyl acrylate or methyl methacrylate. Most preferred copolymers are methacrylic acid copolymers, type C, USP (copolymers of methacrylic acid and ethyl acrylate with methacrylic acid units of 46.0% to 50.6%). Such copolymers are commercially available from Rohm Pharma as Eudragit® L 100-55 (as powder) or L30D-55 (as 30% dispersion in water). Other pH-dependent binder materials that can be used alone or in combination in sustained release formulation dosage forms include hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinylacetate phthalate, polyvinylpyrroli Don phthalate.

One or more pH-independent binders may be used in sustained release formulations in oral dosage forms. pH-dependent binders and viscosity enhancers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly (meth) acrylate esters, etc., are themselves pH-dependent binders as indicated above. It should be noted that it may not provide the required dissolution control provided by. The pH-independent binder may be present in the formulation of the present invention in an amount in the range of about 1 to about 10 weight percent, preferably in an amount in the range of about 1 to about 3 weight percent and most preferably in about 2.0 weight percent. have.

As shown in Table 1, ranolazine or the R- or S-enantiomer of ranolazine is relatively insoluble in aqueous solutions with a pH above about 6.5, while at a pH below about 6 the solubility begins to increase rapidly.

Increasing the pH-dependent binder content in the formulation reduces the release rate of the sustained release form of the compound from the formulation at a pH below 4.5, the typical pH seen above. The enteric coating formed by the binder is less soluble and increases the relative release rate above pH 4.5, with lower solubility of the compound. Properly selected pH-dependent binders significantly affect the release rate at low pH, while increasing the release rate of the compound from the formulation above pH 4.5. Partial neutralization of the binder facilitates the conversion of it into a latex-like film formed around individual granules. Thus, the type and amount of pH-dependent binder and the amount of partially neutralizing composition are selected to closely control the dissolution rate of the compound from the formulation.

Dosage forms of the invention should include an amount of pH-dependent binder sufficient to produce a sustained release formulation in which the release rate of the compound is controlled to significantly slow the dissolution rate at low pH (less than about 4.5). For methacrylic acid copolymers, type C, USP (Eudragit® L 100-55), the appropriate amount of pH-dependent binder is 5% to 15%. The pH dependent binder will typically be about 1 to about 20% of the binder methacrylic acid carboxyl group is neutralized. However, it is preferable that the degree of neutralization is in the range of about 3 to 6%. The sustained release formulation may also contain a pharmaceutical excipient that is intimately admixed with the compound and a pH-dependent binder.

Pharmaceutically acceptable excipients include, for example, pH-independent binders or film formers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly (meth) Acrylate esters (such as methyl methacrylate / ethyl acrylate copolymer sold under the trade name Eudragit® NE by Rohm Pharma), starch, gelatin, sugars, carboxymethylcellulose and the like. Other useful pharmaceutical excipients include: diluents such as lactose, mannitol, dry starch, microcrystalline cellulose and the like; Surfactants such as polyoxyethylene sorbitan ester, sorbitan ester and the like; And colorants and flavoring agents. Lubricants (such as talc and magnesium stearate) and other tableting aids are also optionally present.

Sustained release formulations of the present invention have an active compound content of about 35% to about 95% by weight, about 50% to about 95% by weight, more preferably about 70 to about 90% by weight and most preferably About 70 to about 80 weight percent; the pH-dependent binder content is 5% to 40%, preferably 5% to 25%, and more preferably 5% to 15%; The remainder of the dosage form includes pH-independent binders, fillers, and other optional excipients.

One particularly preferred sustained release formulation of the present invention is shown in Table 2 below.

Sustained release formulations of the invention are prepared as follows: The compound and pH-dependent binder and any optional excipients are mixed intimately (dry blending). The dry blended mixture is then granulated in the presence of a strong base aqueous solution, which is sprayed into the blended powder. The granules are dried, screened, mixed with an optional lubricant (such as talc or magnesium stearate) and compressed to form tablets. Preferred strong base aqueous solutions are solutions of alkali metal hydroxides such as sodium or -potassium, preferably sodium hydroxide in water (optionally containing up to 25% water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with optional film formers for identity verification, taste-masking purposes and to improve ease of swallowing. The film former will typically be present in an amount ranging from 2% to 4% of the tablet weight. Suitable film formers are well known in the art, including hydroxypropyl methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate / methyl-butyl methacrylate copolymer-Eudragit® E-Rohm Pharma). These film formers may optionally contain colorants, plasticizers, and other supplementary ingredients.

Compressed tablets preferably have a hardness sufficient to withstand 8 Kp compression. Tablet size will mainly depend on the amount of compound in the tablet. The tablet will comprise 300 to 1100 mg of the compound free base. Preferably, the tablet will include compound free base in an amount in the range of 400-600 mg, 650-850 mg, and 900-1100 mg.

In order to affect the dissolution rate, the time for wet mixing the compound containing powder is adjusted. Preferably the total powder mixing time, ie the time the powder is exposed to sodium hydroxide solution, will range from 1 to 10 minutes, preferably 2 to 5 minutes. After granulation, the particles are taken out of the granulator and placed in a fluid bed drier and dried at about 60 ° C.

Rather than using the compound as its pharmaceutically more common dihydrochloride salt or another salt or ester thereof, by this method, the peak plasma levels are lowered and still after administration, It has been shown that sustained release formulations are prepared that provide a compound concentration in plasma that is effective over time. There are at least one advantage of using the free base: Since the molecular weight of the free base is only 85% of the molecular weight of the dihydrochloride, it is possible to increase the proportion of the compound in the purification. In this way, delivery of an effective amount of the compound is achieved while limiting the physical size of the dosage unit.

Unit dosage forms specific for R-enantiomers

Intravenous Formulation

In one aspect, the present invention provides an intravenous (IV) solution comprising a selected concentration of R- ranolazine. Specifically, the IV solution preferably contains about 1.5 to about 3.0 mg, more preferably about 1.8 to about 2.2 mg and even more preferably about 2 R-ranolazine per milliliter of a pharmaceutically acceptable aqueous solution. Contains mg.

Oral Formulations

In one embodiment, the R- ranolazine formulation is an oral formulation. In one embodiment, the oral R- ranolazine formulation is a tablet. In one embodiment, the R- ranolazine tablet is 500 mg or less. In a preferred embodiment, the R- ranolazine tablet is 375 mg, and / or 500 mg.

Oral ranolazine formulations are described in U.S. Pat. Patent 6,303,607 and U.S. Pat. It is discussed in detail in publication 2003/0220344, all of which are incorporated herein by reference in their entirety.

Oral sustained release R- ranolazine dosage formulations of the present invention provide plasma ranolazine levels above a threshold treatment level and below a maximum tolerable level (preferably about 550-7500 ng base / mL plasma levels in patients). To be administered 1, 2 or 3 times within a 24 hour period. In a preferred embodiment, the range of plasma levels of ranolazine is about 1500-3500 ng base / mL.

In order to achieve the desired plasma ranolazine levels, it is preferred to administer the oral R- ranolazine dosage forms described herein once or twice a day. When the dosage form is administered twice daily, the oral R- ranolazine dosage form is preferably administered at about 12 hour intervals.

In addition to formulating and administering oral sustained release dosage forms of the invention in a manner that controls plasma ranolazine levels, it is also important to minimize the difference between the highest and trough plasma ranolazine levels. The highest plasma ranolazine levels are typically about 30 minutes to 8 hours or more after the first dose of the dosage form, and the lowest plasma ranolazine levels are near the time of taking the next planned dosage form. The sustained release dosage form of the invention is preferably such that the highest ranolazine level is no more than eight times higher than the lowest ranolazine level, preferably no more than four times higher than the lowest ranolazine level, and preferably the lowest ranol It is desirable to administer in such a way that no more than three times the gin level, and most preferably not more than two times the lowest ranolazine level.

The sustained release R- ranolazine formulations of the present invention provide a therapeutic benefit that allows for up to twice daily administration while minimizing changes in ranolazine concentrations in plasma. The formulations may be administered alone or in combination (at least initially) with immediate release formulations, if desired to rapidly achieve a therapeutically effective plasma concentration of ranolazine, or in soluble IV formulations and oral dosage forms. .

The invention will be further understood by reference to the following examples, which are purely intended as representative examples of the invention. The illustrated aspects are intended to be illustrative only of one aspect of the present invention, and the scope of the present invention is not limited thereto. Any methods that are functionally equivalent are within the scope of the present invention. Various modifications to the present invention other than those described herein will be apparent to those skilled in the art from the foregoing detailed description and the accompanying drawings. Such modifications fall within the scope of the appended claims.

Example 1

Effects of Ranolazine or Ranolazine R- or S-Enantiomers on GSIS of Pancreatic Islets Isolated from Rats

1 shows the effect of ranolazine on GSIS in pancreatic islets isolated from rats. Rat pancreatic islets were isolated from male Sprague-Dawley (SD) rats (8-12 weeks old, n = 6) as described in Yang Z. et al. Transplantation 2004, 77, 55-60. And overnight in RPMI1640 complete medium. Insulin secretion assays were performed essentially as previously described in Liu D. et al. Steroids 2006, 71, 691-699. Briefly, prior to the experiment, the pancreatic islets were treated with Krebs-Ringer bicarbonate buffer (KRB; 129 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO ₄ , 1.2 mM KH ₂ PO ₄ , 2.5 mM CaCl ₂ , 5 mM) containing 3 mM glucose. NaHCO ₃ , 0.1% BSA, 10 mM HEPES, pH 7.4), pre-incubate for 30 minutes, and then wash the pancreatic islets, then in 3-well in 24-well plates (50 pancreatic islets / well), 3 mM Incubate for 60 min at 37 ° C. in the presence of varying concentrations of ranolazine or vehicle in oxygenated KRB buffer containing glucose or 20 mM glucose. Insulin secreted into the experimental sample was measured with the RIA kit (Mercodia, NC).

All insulin secretion data in this study were normalized to insulin secretion per pancreatic islet. There was a biphasic insulin secretion response to ranolazine. At lower concentrations (1 nM to 1 μM) ranolazine increased insulin secretion in a concentration-dependent manner (2-5 fold). Ranolazine had no significant effect on GSIS at a concentration of 10 μM, ie the amount of insulin release was not significantly different from that observed with 20 mM glucose.

Using the procedure described above, R- and S-enantiomers of ranolazine were tested in isolated rat pancreatic islets to show the effect of R- and S-enantiomers of ranolazine on GSIS.

Example 2

Effect of Ranolazine on Insulin Levels in Rats

Figure 2 shows plasma insulin levels during the venous glucose load test (IVGTT) performed in normal SD rats. Each rat was subjected to IVGTT according to the method of Hendrick et al., Metabolism 42, (1): 1-6, 1993. Rats were fasted overnight before test administration. One group of 11 rats received saline only before glucose loading, whereas the second group of 7 rats received ranolazine before glucose loading. Glucose was administered at time 0. Ranolazine was administered at a dose of 15 mg / kg body weight 30 minutes before glucose administration. Blood insulin concentrations were then measured at -30, 0, 2, 4, 7, 15 and 30 minutes. As can be seen from the graph of insulin levels versus time vs. baseline, the insulin levels were higher in ranolazine treated rats compared to vehicle treated rats.

Example 3

Effect of Ranolazine Enantiomers on Insulin Levels in Rats

3 shows insulin levels during the venous glucose tolerance test (IVGTT) performed in normal SD rats. The procedure used the procedure as described in Example 2 above. As can be seen in the graph of insulin vs. time versus baseline, insulin levels were higher in rats treated with R-enantiomers of ranolazine at 15 mg / kg compared to vehicle treated rats. Insulin responses to the S-enantiomers did not differ from vehicle treated rats.

Example 4

Effects of Ranolazine R- or S-Enantiomers on GSIS of Human Pancreatic Islets

4 shows the effect of R-enantiomer of ranolazine (denoted "R-") and S-enantiomer of ranolazine (denoted "S-") on the GSIS of pancreatic islets isolated from humans from a donor Shows. The procedure for human pancreatic islets uses the same procedure as used in Example 1 above, but the incubation period was 30 minutes instead of 60 minutes used in Example 1.

Example 5

Effects of Ranolazine on GSIS of Human Pancreatic Islets

5 shows the effect of (±) ranolazine on GSIS in isolated human pancreatic islets. The procedure for the human pancreatic islets used the same procedure as used in Example 1 above, but the incubation period was 30 minutes instead of 60 minutes used in Example 1. "n" is the number of donors.

Example 6

Effect of Racemic Ranolazine on CYP2D6

Potassium phosphate, pH 7.4 (final concentration = 100 mM), 0.163 mM NADP (nicotinamide adenine dinucleotide phosphate), 1.64 mM G-6-P (glucose-6-phosphate), and 0.4 units / mL glucose-6-phosphate NADPH (nicotinamide adenine dinucleotide phosphate, reduced) regeneration mixture containing dehydrogenase, CYP2D6-specific marker substrate (bufurol, 12.5 μM, or dextromethorphan, 10 μM), ranolazine ( Incubation mixtures containing 10, 25, 50, 100, 250, 500, 1000 μM), or known CYP2D6 inhibitors (quinidine, 1 μM), and human liver microsomal (HLM) protein (0.5 mg / mL) Was used to test the effect of racemic ranolazine on CYP2D6. The substrate, buffer and enzyme were pre-warmed at 37 ° C. The pre-warmed NADPH regeneration system was added and the samples mixed gently and incubated for 30 minutes. Tandem mass spectrometry assays monitored the effect of ranolazine on the CYP2D6 marker response to form 1-hydroxy-bufurol and dextrose. Quinidine, a known CYP2D6 inhibitor, was included as a positive control. The negative control sample consisted of all components except ranolazine or known inhibitors. Incubation was performed in duplicates. Racemic ranolazine (free base form) has an IC ₅₀ (μM) of 324.

Example 7

Effect of Ranolazine R- and S-Enantiomers on CYP2D6

The incubation mixture is potassium phosphate, pH 7.2 (final concentration = 100 mM), magnesium chloride (5 mM), NADPH (1 mM), CYP2D6-specific marker substrate (bufurol, 25 μM), (R) or (S )-Ranolazine (10, 25, 100, 250, 1000 μΜ), or known CYP2D6 inhibitor (quinidine, 5 μΜ), and human liver microsomal (HLM) protein. All reagents except NADPH were combined and preincubated at 37 ° C. for 2-3 minutes. The reaction was initiated by addition of NADPH and incubated for 20 minutes. Bufuralol 1-hydroxylation, a CYP2D6 marker response, was monitored. Quinidine, a known CYP2D6 inhibitor, was included as a positive control. The negative control sample consisted of all components except ranolazine. Incubation was carried out in 3 sets for each condition except for the positive control and 2 sets of positive controls. R- Ranolazine (free base form) has an IC ₅₀ (μM) of 430. S- Ranolazine (free base form) has an IC ₅₀ (μM) of 130.

Example 8

Effect of Ranolazine and R- and S-Enantiomers of Ranolazine on β1 and β2-Adrenergic Receptors.

The purpose of this example is to show the affinity and efficacy of ranolazine and its S- and R-enantiomers for β ₁ and β ₂ -adrenergic receptors (AR) of various tissues and cell lines. Radioligand binding techniques were used to measure competition of these compounds in specific radioligand binding to β ₁ -and β ₂ -AR using membranes prepared from rat ventricular and guinea pig lungs, respectively. The affinity (K _i value) of ranolazine was 8.6 and 14.8 μM for β ₁ -and β ₂ -AR, respectively. S-enantiomers have higher affinity with K _i values for β ₁ -and β ₂ -AR with 4.8 and 6.7 μM, respectively, whereas R-enantiomers have affinity with K _i values> 100 and 39.0 μM, respectively. Much lower.

Effects of Ranolazine and its S- and R-enantiomers on cAMP accumulation in rat C6 glioma cells (mainly β ₁ -AR expression) and DDT ₁ MF-2 hamster smooth muscle cells (mainly β ₂ -AR expression) Was measured. None of the compounds showed any agonist activity, that is, they alone did not increase cAMP accumulation. However, in the presence of these compounds, the concentration-response curve for isoproterenol-induced increase in cAMP shifted to the right without showing a pronounced decrease in maximal response, indicating that these compounds were β ₁ -and β _2- A competitive antagonist against ARs. Using the Schild equation for various concentrations of antagonist (ranolazine) or single concentration of enantiomers, the K _B values for ranolazine and its S- and R-enantiomers are 9.7, 8.0, and> 50 μΜ (for β ₁ -AR) and 12.2, 9.0, and> 50 μΜ (for β ₂ -AR). In short, ranolazine and its S-enantiomers are competitive antagonists for β ₁ and β ₂ -ARs, and S-enantiomers have the highest binding affinity among them.

Example 9

R- and S-enantiomers of ranolazine are I _Kr , I _Ks , And I _Na  Impact on

The purpose of this example is to demonstrate the effect of S- and R-enantiomers of ranolazine on I _Kr , I _Ks , and late I _Na . Whole cell current was measured at 37 ° C. from midmyocrdial cells isolated from dogs. I _Kr and I _Ks were measured during the standard pulse protocol. Late I _Na was measured using an action potential measured with a basic cycle length (BCL) of 300 and 2000 ms as the command waveform during the voltage clamp. Enantiomeric effects were measured at concentrations of 3, 10, and 30 μM.

Late I _Na was evaluated at two voltages during the plateau and final repolarization of the voltage fixation action potential. S- and R- ranolazine inhibited late I _Na in a concentration-dependent manner. Like racemic ranolazine, inhibition by the enantiomers was greatest at high plateau potentials and during rapid stimulation. At a BCL of 300, half-inhibition of late I _Na by S- ranolazine and R- ranolazine (IC ₅₀ ) occurred at 5 ± 0.4 μM and 8 ± 2.6 μM, respectively (R vs S, ns). IC ₅₀ for I _Kr was 10 ± 2 μM for S-Ranolazine and 28 ± 4 μM for R-Ranolazine (R vs S; p <0.05). I _Ks was reduced by 27% by 30 μM S- _Ranolazine , whereas the same concentration of R- _Ranolazine reduced I _Ks by only 5% (p <0.004). As a comparison, a racemic granola Truesilver reviews IC ₅₀ values for the IC ₅₀ is 11 μM, and I _Ks for the IC ₅₀ 5 μM, I _Kr on I _Na is> was found to be 100 μM (reference: Zygmunt (2002) Pacing Clin. Electrophysiol 25, II-626, Abstract). In conclusion, R- _ranolazine blocks I _Kr and I _Ks less than S- ranolazine or racemic forms of the drug and inhibits them almost equally for late I _Na .

Example 10

Effect of Ranolazine and R- and S-Enantiomers of Ranolazine on LV MAPD

The purpose of this example is that ranolazine and the R- and S-enantiomers of ranolazine result in left ventricular monophasic action potential period (LV MAPD), local LV dispersion (MAP) and arrhythmia development of MAPD. This is to indicate the effect on the system. Hearts isolated from female rabbits were perfused with modified KH solution and paced at a constant rate of 1 Hz after surgically inducing complete atrioventricular block. LV MAP from the deep bottom and the apex was measured using a contact MAP electrode. Ranolazine (1-100 μM) is similar for ventricular and atrial MAPD ₉₀ without increasing local MAPD variance or inducing premature ventricular beat (PVB) or ventricular tachycardia (VT). It resulted in a concentration-dependent prolongation, ie EC ₅₀ of 4.3 and 4.8 μmol / L (n = 7), respectively, leading to a 32 ± 4% and 35 ± 4% increase over the control. The enantiomers of ranolazine, R and S, extended MAPD ₉₀ by up to 22 ± 5 and 28 ± 4% increase (n = 11 and 9, respectively).

matter

Ranolazine, (±) -N- (2,6-dimethylphenyl)-(4 [2-hydroxy-3- (2-methoxyphenoxy) propyl] -1-piperazine (Lot # E4-NE -002), Ranolazine R-isomer (Lot # SAR-224-12-6) and S-isomer (Lot # SAR-224-24-11) are the Bioorganic Chemistry Department (Palo Alto, CV Therapeutics, Inc.). CA) E-4031 (l- [2- (6-methyl-2-pyridyl) ethyl] -4-methylsulfonylaminobenzoyl) piperidine, Lot # E-04) and ATX- II (Anemonia sulcata, Lot # AT-04) was purchased from Alomone Labs (Jerusalem, Israel). Dimethylsulfoxide (100% DMSO; Sigma, St. Louis, MO) was used to prepare a stock solution of 40 mmol / L concentrations of ranolazine and its R and S isomers. ATX-II and E-4031 were dissolved in saline to prepare 10 μmol / L and 1 mmol / L stock solutions, respectively. All solutions were stored at −4 to −20 ° C. and diluted in physiological saline before use. The final DMSO content in the final solution used for perfusion to the heart was <0.1%. Female rabbits (New Zealand White species, 2.5-3.5 kg) were obtained from Western Oregon Rabbitry (Philomath, OR). CV Therapeutics, Inc. Inspected and approved by the Institutional Animal Care and Use Committee.

Experiment preparation

Each animal was sedated using 6 mg / kg xylazine intramuscular injection (im) and 40 mg / kg ketamine intramuscular injection, followed by “cocktail” (15 mg / kg + 15 xylazine in ketamine in 1.5 mL saline) through the marginal ear vein. 4 mg / kg) by intravenous injection (iv). The rib cage quickly opened. The heart was excised and placed in modified Krebs-Henseleit (KH) solution at room temperature. The KH solution contained (in mmol / L): NaCl 118, KCl 2.8, KH ₂ PO ₄ 1.2, CaCl ₂ 2.5, MgSO ₄ 0.5, Pyruvate 2.0, Glucose 5.5, Na ₂ EDTA 0.57 and NaHCO ₃ 25. Continue to inject 95% O ₂ and 5% CO ₂ gas into the solution and adjust its pH to 7.4. The catheter was quickly inserted into the aorta and the KH solution warmed to 36-36.5 ° C. was perfused to the heart at a rate of 20 mL / min using a Langendorff method using a roller pump (Gilson Minipuls 3, Middleton, WI). Perfusion pressure was measured from the lateral port of the aortic catheter (using Biopac MP 150 pressure transducer (Goleta, CA)). In order to facilitate the discharge of fluid from the chamber of the left ventricle LV, the valve leaves of the mitral valve were cut out using delicate spring handle scissors. AV conduction was blocked by partial removal of the right atrium for AV nodule resection.

Surgical resection (heating) of the AV nodule zone induced complete AV blockage. The spontaneous ventricular rate (ie ventricular deviation) was a few beats per minute after successful AV nodule resection. Bipolar Teflon-coated electrodes were placed on the right ventricular septum to tune the heart rate. Grass S48 stimulator (W. Warwick, RI) was used to deliver the electrical stimulation at 3 msec intervals and three times the threshold size to the tuning electrode at a frequency of 1 Hz.

After initiation of ventricular tuning, a 30-40 minute delay was allowed to allow the heart rhythm and perfusion pressure to reach a steady state, which is an essential experimental condition for measuring good quality monophasic action potential (MAP). The total duration of this experimental protocol was limited to 2.5 h, during which time the preparation showed good stability.

Signal Measurement and Processing

Monophasic Action Potential (MAP) and Harvard Apparatus Inc. Left ventricular MAP and bipolar ECG were measured using an ECG electrode from (Holliston, Mass.). Two MAP electrodes were placed on the epicardial ventricular free wall below the atrioventricular valve height to measure the deep bottom MAP and apical MAP signals, respectively. The MAP electrodes were pressure-contacting Ag-AgCl electrodes attached to a spring-loaded circular holder that maintains contact between the electrode and the LV epicardial surface. Electrode signals were amplified and shown on a computer monitor and monitored visually throughout the experiment. MAP duration (100% from depolarization initiation) using on-screen calipers throughout each drug infusion period to ensure that each response to drug (s) reaches steady state prior to drug concentration changes. Until repolarization). The signals were stored on a computer hard disk for subsequent analysis. Bipolar electrocardiogram (ECG) was generated using a separate-heart ECG instrument (Harvard Apparatus, Holliston, Mass.) Attached to the Biopac amplifier system. Coronary perfusion pressure was measured using a pressure transducer (Biopac or PowerLab pressure measurement system). Amplify MAP, ECG, and coronary perfusion pressure (CPP) signals properly, remove noise, sample, digitize in real time (using Biopac MP 150 (Goleta, CA)), and display on a computer screen It was. All signals were stored on the computer hard disk for subsequent analysis.

Using computer software (Biopac, Goleta, Calif.), The initial MAP profiles for successive 3-5 beats are superimposed to obtain one average signal, which is then plotted by moving it to Microsoft Excel software for repolarization. The duration of MAP at 90% complete level (MAPD ₉₀ ) was measured.

Exclusion Criteria

Preparations were excluded from this study if any of the following problems occurred during the equilibrium period: (1) unstable coronary perfusion pressure; (2) persistent ventricular premature contraction (PVB) or ventricular tachycardia after AV nodule resection; (3) anatomical damage to the heart as seen with the naked eye; Or (4) MAP signal instability. Approximately 5% of all preparations were excluded.

Statistical analysis

All data are reported as mean ± SEM. Concentration-response curves were analyzed using Prism Version 3.0 (GraphPad, San Diego, Calif.). Repeated One-Way ANOVA was used to compare measurements from the same heart before and after drug treatment (SigmaStat, IL). When the ANOVA showed a significant difference between the measurements, the Student-Newman-Keuls test and the Student t-test were applied to determine which paired group mean significantly differed. Significant difference between two group means was defined as p <0.05. To facilitate the interpretation of drug response in different hearts, the effects of the drugs were sometimes calculated as a percentage change over the control.

Testing with Ranolazine and R- and S-Enantiomers

Increasing the concentration of ranolazine and its R- and S-enantiomers (concentration range for each drug: 0.1-100 μmol / L), between 7-15 between changes in the ranolazine concentration to achieve a steady state effect Minutes were injected into the rabbit heart in a cumulative fashion to build a concentration-MAPD ₉₀ response curve. All hearts were tuned at 1 Hz over the entire duration of this experimental procedure. Maximum MAP prolongation was measured during each concentration of drug infusion.

LV depth and tip MAP were simultaneously measured over the entire duration of the experiment. MAP duration (MAPD ₉₀ ) from the bottom and the apex at the repolarization 90% completion level was measured to compare local LV MAPD variance, MAP prolongation induced by each drug.

Ranolazine extended MAPD ₉₀ measured in a rabbit left ventricle tuned to 1 Hz in a concentration-dependent manner. The maximum increase in deep and apex MAPD ₉₀ was similar as 32.2 ± 4.2% and 35.2 ± 4.1% (n = 7, p <0.01) compared to the control (no drug) at ranolazine concentrations of 30-100 μmol / L, respectively. . The estimated potency (EC ₅₀ value) of ranolazine to extend LV MAPD ₉₀ (bottom and tip) was 4.3 and 4.8 μmol / L, respectively. Ranolazine did not induce any EAD, PVB or VT at any concentration.

R and S, enantiomers of ranolazine, also extended MAPD ₉₀ with up to 22 ± 5 and 28 ± 4% increase, respectively. The EC ₅₀ extending LV MAPD ₉₀ in the R and S isomers was 6.4 and 5.9 μmol / L, respectively, suggesting that the S isomer is more potent than the R isomer.

Claims (45)

A method of enhancing endogenous insulin levels in a patient in need of enhancing endogenous insulin levels, comprising administering to the patient an ranoxazine or R- or S-enantiomer of ranolazine as an amount of racemate to enhance insulin secretion. . The method of claim 1, wherein the patient is insulin-reactive and lacks insulin secretion. The method of claim 2, wherein the patient is prediabetes or otherwise a patient prone to diabetes. The method of claim 2, wherein the patient is suffering from type II diabetes. 2. The method of claim 1 wherein the amount of ranolazine that enhances insulin secretion is in the racemate form. The method of claim 1, wherein the amount of ranolazine that enhances insulin secretion is in the R- or S-enantiomer form of ranolazine. 7. The method of claim 6 wherein the amount of ranolazine that enhances insulin secretion is the R-enantiomer form of ranolazine. A method of reducing the amount and / or frequency of insulin administration to a patient comprising administering to the patient a ranolazine or R- or S-enantiomer of ranolazine as a racemate in an amount that enhances insulin secretion. The method of claim 8, wherein the amount of ranolazine that enhances insulin secretion is in the racemate form. The method of claim 8, wherein the amount of ranolazine that enhances insulin secretion is the R-enantiomer form of ranolazine. A method of treating diabetic patients, comprising administering to a patient a combination of at least one antidiabetic agent with ranolazine or ranolazine as a racemate in an amount that enhances insulin secretion, or the R- or S-enantiomer of ranolazine. . The method of claim 11, wherein the amount of ranolazine that enhances insulin secretion is in the racemate form.  The method of claim 11, wherein the amount of ranolazine that enhances insulin secretion is the R-enantiomer form of ranolazine. Maintaining the effectiveness of anti-diabetic treatment in a patient, comprising administering to the patient a combination of anti-diabetic agents with the R- or S-enantiomer of ranolazine or ranolazine as an amount of racemate to enhance insulin secretion How to let. 15. The method of claim 14, wherein the amount of ranolazine that enhances insulin secretion is in the racemate form. 15. The method of claim 14 wherein the amount of ranolazine that enhances insulin secretion is the R-enantiomer form of ranolazine. A composition comprising ranolazine or R- or S-enantiomer of ranolazine as a racemate in an amount that enhances insulin secretion and at least one antidiabetic agent. 18. The composition of claim 17, wherein the amount of ranolazine that enhances insulin secretion is in the racemate form.  18. The composition of claim 17, wherein the amount of ranolazine that enhances insulin secretion is in the form of the R-enantiomer of ranolazine. 18. The composition of claim 17, wherein said antidiabetic agent is selected from the group consisting of: sulfonylureas, DPP-IV inhibitors, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, incretin mimetics, PPARs Gamma modulator, dual PPARalpha / gamma agonist, RXR modulator, SGLT2 inhibitor, aP2 inhibitor, insulin sensitizer, PTP-IB inhibitor, GSK-3 inhibitor, DP4 inhibitor, insulin sensitizer, insulin, meglitinide, PTP1B inhibitor, glycogen Phosphorylase inhibitors, glucose-6-phosphatase inhibitors, and amylin analogs. 21. The composition of claim 20, wherein the antidiabetic agent is selected from the group consisting of: metformin, phenformin, buformin, chlorpropamide, glyoxepide, glyburide, acetohexamide, chlorpropamide , Glyborneuride, tolbutamide, tolazamide, glypide, glymepiride, glyclazide, glyquidone, glyhexamide, fenbentamide, tolcyclamid, troglitazone, pioglitazone, rosiglitazone, miglitol, acar Boss, exenatide, bilagliptin, citagliptin, repaglinide, pramlinted, and nateglinide. The method of claim 11, wherein the antidiabetic agent is selected from the group consisting of: sulfonylureas, DPP-IV inhibitors, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, incretin mimetics, PPARs Gamma modulator, dual PPARalpha / gamma agonist, RXR modulator, SGLT2 inhibitor, aP2 inhibitor, insulin sensitizer, PTP-IB inhibitor, GSK-3 inhibitor, DP4 inhibitor, insulin sensitizer, insulin, meglitinide, PTPlB inhibitor, glycogen Phosphorylase inhibitors, glucose-6-phosphatase inhibitors, and amylin analogs. 23. The method of claim 22, wherein the antidiabetic agent is selected from the group consisting of: metformin, phenformin, buformin, chlorpropamide, glyoxepid, glyburide, acetohexamide, chlorpropamide , Glyborneuride, tolbutamide, tolazamide, glypide, glymepiride, glyclazide, glyquidone, glyhexamide, fenbentamide, tolcyclamid, troglitazone, pioglitazone, rosiglitazone, miglitol, acar Boss, exenatide, bilagliptin, citagliptin, repaglinide, pramlinted, and nateglinide. 15. The method of claim 14, wherein said antidiabetic agent is selected from the group consisting of: sulfonylureas, DPP-IV inhibitors, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, incretin mimetics, PPARs Gamma modulator, dual PPARalpha / gamma agonist, RXR modulator, SGLT2 inhibitor, aP2 inhibitor, insulin sensitizer, PTP-IB inhibitor, GSK-3 inhibitor, DP4 inhibitor, insulin sensitizer, insulin, meglitinide, PTP1B inhibitor, glycogen Phosphorylase inhibitors, glucose-6-phosphatase inhibitors, and amylin analogs. 25. The method of claim 24, wherein the antidiabetic agent is selected from the group consisting of: metformin, phenformin, buformin, chlorpropamide, glyoxepide, glyburide, acetohexamide, chlorpropa Mead, glyborneuride, tolbutamide, tolazamide, glypide, glymepiride, glyclazide, glyquidone, glyhexamide, fenbentamide, tolcylamide, troglitazone, pioglitazone, rosiglitazone, miglitol, a Carbos, exenatide, bilagliptin, citagliptin, repaglinide, pramtinide, and nateglinide. A method of treating a patient suffering from one or more cardiovascular diseases, comprising administering an R-enantiomer of ranolazine to these patients, which enhances endogenous insulin levels while reducing adverse events and / or drug-drug interactions. How to let. The method of claim 26, wherein the administration is oral. The method of claim 27, wherein the R-enantiomer of ranolazine is administered as a sustained release formulation.  The method of claim 27, wherein the R-enantiomer of ranolazine is administered as an immediate release formulation. The method of claim 1, wherein the patient is treated with the R-enantiomer of ranolazine without testing the patient to determine if there is a malfunction of the CYP2D6 enzyme. 27. The method of claim 26, wherein the at least one cardiovascular disease or cardiovascular disease symptom is selected from: heart failure, ventricular tachycardia such as atrial fibrillation, atrial fibrillation, including congestive heart failure, acute heart failure, myocardial infarction, and the like. Arrhythmia, exercise-, including treatment of ventricular tachycardia (VT), including AV nodular regressive tachycardia, atrial tachycardia, and idiopathic ventricular tachycardia, ventricular fibrillation, premature-excited syndrome, and Torsard de Point (TdP) Peripheral artery disease, including angina, heterogeneous angina, stable angina, unstable angina, acute coronary syndrome, and the like, and intermittent claudication. The method of claim 26, wherein the patient is insulin-reactive and lacks insulin secretion. 33. The method of claim 32, wherein the patient is prediabetes or otherwise susceptible to diabetes. 33. The method of claim 32, wherein the patient is suffering from type II diabetes. A pharmaceutical composition comprising a therapeutically effective amount of the R-enantiomer of ranolazine or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof. A method of treating a patient suffering from one or more cardiovascular diseases, comprising administering an S-enantiomer of ranolazine to these patients, the method of reducing adverse events. The method of claim 36, wherein the administration is oral. 38. The method of claim 37, wherein the S-enantiomer of ranolazine is administered as a sustained release formulation. 38. The method of claim 37, wherein the S-enantiomer of ranolazine is administered as an immediate release formulation. The method of claim 36, wherein the at least one cardiovascular disease or cardiovascular disease symptom is selected from: heart failure, including congestive heart failure, acute heart failure, myocardial infarction, etc., ventricular tachycardia such as atrial fibrillation, atrial fibrillation, AV Arrhythmia, exercise-induced, including treatment of nodular regressive tachycardia, atrial tachycardia, and ventricular tachycardia (VT), including idiopathic ventricular tachycardia, ventricular fibrillation, premature-excited syndrome, and Torsard point (TdP) Angina pectoris, including angina pectoris, heterotypic angina pectoris, stable angina pectoris, unstable angina pectoris, acute coronary syndrome, and the like, and peripheral arterial disease, including intermittent claudication. 37. The method of claim 36, wherein the patient is a diabetic, prediabetes, or otherwise susceptible to diabetes mellitus, and administering a therapeutically effective amount of the R-enantiomer of ranolazine in an amount different from that of the S-enantiomer. Including as. 42. The method of claim 41, wherein the patient is prediabetes or otherwise susceptible to diabetes. 42. The method of claim 41, wherein the patient is suffering from type II diabetes. A pharmaceutical composition comprising a therapeutically effective amount of S-enantiomer of ranolazine or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof. A pharmaceutical composition comprising R-enantiomers and S-enantiomers of ranolazine in therapeutically effective amounts of ranolazine or pharmaceutically acceptable salts, esters, prodrugs, or hydrates thereof.

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